CHROMATIN TARGETS FOR CANCER THERAPY

描述：（申请人的描述） 腺病毒ElA癌蛋白在芽殖酵母中的表达提供了 这是一个发现癌蛋白作用新途径的有用模型。 值得注意的是，多蛋白复合物（SWI/SNF和HAT复合物），介导 EIA靶向染色质重塑和转录调节， 这导致了一个强烈的预测，即人类的破坏是 在癌症的发展中起着重要作用。 的确，有证据表明， 系统，癌症的发展与损失或 编码几种SWI/SNF和HAT组分的基因失调 配合物鉴于“染色质动力学”在细胞中的明确作用， 调节及其在肿瘤发生中的遗传参与， 控制染色质功能可能包含抗癌药物的有用靶点 疗法这项建议旨在扩展以前的工作，对致癌相关的 酵母中的途径，并确定具有抗癌作用的新化合物 治疗潜力 染色质缺陷明确的酵母菌株 重塑功能将受到两个高通量筛选， 库：来自美国的大约2000种化合物的“多样性集”。 国家癌症研究所的发展治疗计划，和一个图书馆 约6000乙醇植物提取物可通过 弗吉尼亚大学马基细胞信号中心。探明 酿酒酵母在阐明新的致癌相关基因中的应用 通路将允许对新的先导化合物的作用进行遗传解剖 药物筛查的结果先导化合物将在哺乳动物细胞中进一步测试 培养系统，以检查其作为治疗剂的潜力， 对哺乳动物染色质动力学的特殊影响。

DESCRIPTION: (Applicant's Description) Expression of the adenovirus ElA oncoprotein in budding yeast has provided a useful model for uncovering novel pathways involved in oncoprotein action. Remarkably, multiprotein complexes (SWI/SNF and HAT complexes) that mediate chromatin remodeling and transcriptional regulation are targeted by EIA, leading to the strong prediction that disruption their human counterparts is important in the development of cancer. Indeed, there is evidence from human systems that the development of cancer is associated with loss or disregulation of genes encoding components of several SWI/SNF and HAT complexes. Given the clear role of "chromatin dynamics" in cellular regulation, and its genetic involvement in oncogenesis, the pathways which control chromatin function may contain useful targets for anti-cancer drug therapy. This proposal seeks to extend previous work on oncogenesis-related pathways in yeast, and to identify novel compounds with anti-cancer therapeutic potential. Yeast strains with defined defects in chromatin remodeling functions will be subjected to high throughput screens of two libraries: The "Diversity Set" of approximately 2000 compounds from the National Cancer Institute's Developmental Therapeutics Program, and a library of approximately 6000 ethanolic botanical extracts available through the Markey Center for Cell Signaling at the University of Virginia. The proven utility of Saccharomyces cerevisiae for illuminating novel oncogenesis-related pathways will allow genetic dissection of the action of novel lead compounds from the drug screens. Lead compounds will be tested further in mammalian cell culture systems to examine their potential as therapeutic agents, and their specific effects on mammalian chromatin dynamics.